Juvenile rheumatoid arthritis (JRA) is a prevalent pediatric condition and the most common cause of non-accidental acquired blindness in children. The etiology of JRA is unknown, but there is a genetic predisposition JRA is an inflammatory disease as evidenced by the presence of proinflammatory cytokines in the synovial fluid or synovium of affected joints. Two types of T helper subsets have been identified based on the profile of cytokines they produce. Th1 cells secrete predominately interferon-gamma (IFYgamma) and interleukin (IL)-2, while Th2 cells secrete predominately IL-4, IL-5, Il-13, and IL-10. IL-4 is a multifunctional cytokine secreted by Th2 cells and mast cells. IL-4 activates germline transcription of from the epsilon heavy chain locus and, together with signals delivered via the B cell surface molecule CD40, induces isotype switching from mu to epsilon. Studies both in vivo and in vitro have demonstrated that IL-4 is critical for the development of Th2 cells. This results in an amplification loop that perpetuates the Th2 response since IL-4 promotes Th2 development and ultimately the release of more IL-4. Recently, there have been several reports suggesting that JRA is predominantly a Th1-type disease. Since Th2 cytokines, and specifically IL-4, have been reported to have a protective effect in JRA, functionally relevant allelic variations in the IL-4Ralpha may have important roles in the genetics and pathogenesis of JRA. The longterm objective of these studies is to determine the functional consequences of the different IL-4Ralpha alleles and to delineate their role in the pathogenesis of JRA. These studies will provide novel insights into the pathogenesis and genetics of JRA. Furthermore, since the IL-4Ralpha and two of its alleles have been linked to atopic disease, it would be very interesting and novel to find the same alleles that predispose to one disease, i.e. atopy, may be protective in another disease, i.e. JRA. This would suggest an evolutionary balance between "disease susceptibility" and "disease protective" genes.